Ischemic heart disease is a leading cause of mortality in the United States and accounts for 1 in 8 deaths. While several experimental and clinical studies have shown improvements in heart function after CSC transplantation, the therapeutic efficacy of these cells may be limited by co-morbid conditions, such as obesity and diabetes. In the US, a large percentage of patients with heart failure have Type 2 diabetes (T2D); however, we do not understand how metabolic dysregulation associated with the conditions of obesity and diabetes affect CSC therapy. Our preliminary data show that CSCs maintain relatively high rates of glycolysis, and although they express functional insulin receptors, their glucose transport is not regulated by insulin. As a result, their glycolytic activity increases during hyperglycemia, and the efficacy of CSC therapy is attenuated in obese-hyperglycemic mice. We have also found that prolonged exposure to hyperglycemia in diabetic mice upregulates CSC glycolysis and prevents CSC proliferation and differentiation. Moreover, diabetic CSCs transplanted into non-diabetic mice appear to worsen infarct-induced heart failure. Based on these observations, we propose that excessive glycolysis promotes stem cell dormancy, prevents differentiation, and diminishes the reparative capacity of CSCs. To test this hypothesis, we will: (1) determine how experimental modulation of glycolytic activity affects CSC function; (2) elucidate the mechanism by which diabetes affects CSCs; and (3) delineate the contribution of glycolysis to CSC therapy in diabetic mice. Results of this project will identify key metabolic pathways that regulate CSC function and competence and elucidate how they are affected by disease conditions such as diabetes and insulin resistance. We expect to identify specific metabolic factors that regulate the efficacy of CSC therapy and to delineate metabolic strategies to enhance CSC-mediated myocardial repair. This understanding will help facilitate the optimization of cell therapy protocols for both diabetic and non-diabetic patients and provide new direction to ongoing and future clinical trials.